PROJECT SUMMARY/ABSTRACT This application for a mentored patient-oriented research career development award will provide the applicant ? a clinical psychologist with a strong background in experimental psychopathology and cognitive-behavioral therapy and growing expertise in non-invasive brain stimulation ? with advanced training, mentored research experience, and protected research time. This will facilitate the applicant's long-term goal: to reduce the mental health burden associated with pathological fear and anxiety by developing novel treatments and augmentation strategies. The candidate proposes: 1) a training plan to gain expertise in translational clinical neuroscience: I) neurobiology and cognitive neuroscience, II) neuroimaging, and III) non-invasive brain stimulation; 2) a mentoring and consultation team with expertise in these three areas; 3) two mentored research projects that will test whether transcranial direct current stimulation (tDCS) can enhance neural and cognitive mechanisms underlying exposure-based treatments for pathological fear and anxiety. The negative valence systems of acute threat (fear), potential threat (anxiety), and sustained threat are among the most clinically important research domain constructs. Psychiatric disorders characterized by pathological fear and anxiety are common, and often disabling. Despite their limitations, exposure therapies are among the most efficacious treatments for these disorders. Extinction learning is thought to be a core mechanism of therapeutic exposure. Extinction learning is mediated by a well-defined circuit encompassing the medial prefrontal cortex, amygdala, and hippocampus. This raises the exciting possibility that direct engagement of this circuitry might enhance the response to therapeutic exposure. tDCS is a neuromodulation technology that can augment synaptic plasticity, learning, and memory. The proposed studies will employ an experimental therapeutics framework to assay mechanisms of action behind therapeutic exposure and evaluate whether tDCS engages these mechanisms. Study 1 will enroll 62 healthy volunteers to test whether tDCS applied to the mPFC can augment spontaneous mPFC activity (Aim 1), functional engagement of extinction circuitry during extinction learning and recall (Aim 2), and classically-conditioned extinction learning (Aim 3). Study 2 will enroll 32 patients diagnosed with obsessive- compulsive disorder (OCD) who will complete a novel behavioral paradigm that encapsulates the core features of exposure therapy for OCD, to test whether tDCS applied to the mPFC enhances exposure-relevant extinction learning (Aim 4). Pathological fear and anxiety directly affect more than one out of every four Americans. Existing treatments are frequently inadequate and need to be improved. The proposed studies will evaluate the ability of tDCS to engage neural and cognitive targets that underpin therapeutic exposure for disordered anxiety. This synergy may improve treatment outcomes for individuals suffering from pathological fear and anxiety.